Role of long non-coding RNA Gas5 in cocaine action

Long non-coding RNAs (lncRNAs) are a class of transcribed RNA molecules greater than 200 nucleotides long. Though do not encode proteins, they play functional roles in gene expression regulation. LncRNAs are notably abundant in the brain, however, their neural functions are largely unknown. Here we demonstrate that repeated short- and long-term cocaine administrations all decreased the expression of lncRNA Gas5 in the nucleus accumbens (NAc) of adult male mice. To illustrate the functional role of Gas5, we performed viral mediated overexpression of Gas5 in the NAc and found decreased cocaine-induced conditioned place preference. Furthermore, Gas5 overexpression also led to decreased drug intake, lower motivation, repressed compulsivity to acquire cocaine, and faster extinction of drug during cocaine self-administration. Transcriptome profiling identified numerous Gas5 mediated gene expression changes that are enriched in relevant neural function categories. Interestingly, these Gas5 regulated gene expression changes significantly overlap with chronic cocaine induced transcriptome alterations, which suggests that Gas5 may serve as a main transcription regulator of cocaine response. Our study therefore displays a novel lncRNA based molecular mechanism of cocaine action. Overall design: Transcriptome profilling of 6 Nucleus Accumbens tissue from mouse brain samples. 3 samples had viral mediated overexpression of Gas5 and 3 control samples received a GFP construct as control, with HSV as the viral vector.